A number of clinical conditions have in common the prospect for successful treatment by balloon catheterization to restore useful configuration to internally distorted vessels. The most prominent application of this technique is in the treatment of coronary artery disease.
Percutaneous transluminal coronary angioplasty (PTCA) has been demonstrated to provide an effective alternative to coronary bypass surgery in relieving stenoses of atherosclerotic plaque within coronary arteries. In this procedure, an inflatable balloon at the distal end of a catheter is positioned in the region of a stenosis. The balloon is inflated under fluid pressure to reconfigure the narrowed lumen and permit increased blood flow through the affected artery. It is not unusual that inflation-deflation cycles will be repeated several times where the narrowing is severe. This mechanical violence to the arterial wall may produce the desired opening of the artery, but in delayed consequence the procedure is followed by a 30-50% incidence of restenosis at or near the injured site. No pharmacologic or mechanical intervention has proven effective in addressing this problem.
Studies have suggested a number of causes underlying restenosis. These studies have indicated that angioplasty may produce endothelial denudation, injury to the vascular wall and rupture of the vasa vasorum. The accompanying uncontrolled proliferation of smooth muscle cells within the arterial wall has been widely implicated as a prominent factor in the resulting restenosis.
Among approaches to dealing with such restenoses has been the delivery of smooth muscle cell growth regulators, such as heparin, to the artery wall at the site of actual or incipient restenosis following angioplasty. U.S. Pat. No. 4,824,436 (Wolinsky) describes a catheter and its use for pressurized local delivery of heparin in solution. Local delivery of heparin and penetration within the arterial wall has been demonstrated by Wolinsky, "Use of A Perforated Balloon Catheter To Deliver Concentrated Heparin Into The Wall Of The Normal Canine Artery," J. Am. Coll. Cardiol. 15:475 (Feb. 1990). However, such a method does not afford sufficient contact at the site of an angioplasty before the drug diffuses to ineffective concentrations.
To increase residence time and provide localized inhibiting activity of heparin in controlling smooth muscle cell proliferation, Edelman et al., "Effect Of Controlled Adventitial Heparin Delivery For Smooth Muscle Cell Proliferation Following Endothelial Surgery," Proc. Natl. Acad. Sci. 87:3773 (May 1990), have implanted heparin in a polymer matrix directly on the adventitia as a means for obtaining local and sustained release of the smooth muscle cell inhibitor. This approach does not lend itself to treating restenosis in humans since it involves a surgical procedure.
Adaptations of balloon catheters also may be used in such conditions as benign prostatic hypertrophy, malignant disorders of various tissues available to tubular access, occlusions in peripheral vasculature, clearing and restoring prostatic and other intrusions in the urethra, opening fallopian tubes and dilating esophageal structures. Such interventions frequently have in common the need for repetitive treatment. The problems that typically arise in practice or in concept are the difficulty of delivery and the provision of adequate residence time in the face of inevitable and premature loss of drug from the desired site through rapid diffusion or erosion.
It is therefore an object of this invention to provide method and compositions for delivering a drug for sustained release at a desired intramural site by injection into the access vessel.
Another object is to provide a method and compositions for delivering a drug to the desired intramural site in a biodegradable polymeric carrier.
A further object is to provide method and compositions for delivering a smooth muscle cell inhibitor for sustained release in the region of a restenosis following angioplasty.